title: Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors.
abstract: OBJECTIVE
  The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.
  
  
  METHODS
  Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.
  
  
  RESULTS
  Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R-signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.
  
  
  CONCLUSIONS
  We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials.
authors.affiliation: Department of General Pathology, University Hospital Heidelberg, Heidelberg, Germany. m.breinig@dkfz-heidelberg.de
authors.forename: Marco
authors.initials: M
authors.lastname: Breinig
authors.forename: Philipp
authors.initials: P
authors.lastname: Mayer
authors.forename: Andreas
authors.initials: A
authors.lastname: Harjung
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.forename: Mona
authors.initials: M
authors.lastname: Malz
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Olaf
authors.initials: O
authors.lastname: Neumann
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dienemann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Michael André
authors.initials: MA
authors.lastname: Kern
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Ralf Joachim
authors.initials: RJ
authors.lastname: Rieker
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077156:Gefitinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C112765:tanespimycin; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib